TMEM176A and TMEM176B Are Candidate Regulators of Inhibition of Dendritic Cell Maturation and Function after Chronic Spinal Cord Injury

Abstract

Inhibition of dendritic cell maturation and activation, together with abnormal functioning of cell-mediated immunity, has been reported in chronic spinal cord injury (SCI). The development of immune-based therapies could: 1) prevent or slow down limit further tissue damage in chronic SCI, and 2) promote tissue regeneration. To identify novel candidate molecular pathways mediating SCI-induced immune changes, we performed whole-genome microarray and molecular pathway analyses. Subjects with motor complete chronic SCI (> 2 years post-injury) and uninjured controls were selected from an ongoing study. Microarray analysis was performed with RNA extracted from circulating monocytes. Partek Genomic Suite (PGS) software was used to limit the 54,000 gene list to only those genes up-regulated or down-regulated by 2-fold or more in SCI compared with control. Pathway analyses were performed with Ingenuity Systems IPA software to identify biological pathways of interest involving differentially expressed genes. Genes of interest were then confirmed by quantitative PCR (qPCR). Six SCI subjects and five uninjured controls were included in the final analyses. A molecular pathway related to immune cell trafficking was identified as being significantly upregulated in the SCI subjects. Two genes in that network, transmembrane domain protein (TMEM)176A and TMEM176B, were notable for the magnitude of overexpression. Dendritic cells have been shown to mediate recovery and/or protective autoimmunity in central nervous system injuries and have the capacity to induce neuroprotection and neurogenesis in stroke patients. High TMEM176A and TMEM176B levels have been shown to prevent dendritic cell maturation and inhibit dendritic cell activity in the general population. Here, we report overexpression of both genes in SCI compared with control subjects. Thus, we propose that TMEM176A and TMEM176B are candidate genes involved in inhibiting protective immune responses in SCI. This study may support future research aimed at developing new targets for therapies to promote immune systemmediated neuroprotection and recovery in SCI.

Single-Cell RNA Sequencing Reveals the Expansion of Cytotoxic CD4+ T Lymphocytes and a Landscape of Immune Cells in Primary Sjögren’s Syndrome

“…Chromosome X Open Reading Frame 21 (CXorf21) has been observed to be a susceptibility gene in SLE ( 34 ), and here, Chromosome 11 Open Reading Frame 31 ( C11orf31 ) and Chromosome 1 Open Reading Frame 162 ( C1orf162 ) were broadly expressed in subtypes of T and B cells and monocytes. TMEM176A and TMEM176B , which were suggested to inhibit DC maturation in chronic spinal cord injury ( 35 ), were expressed in three subtypes of monocytes. Genome-wide association studies (GWASs) reported that the genetic locus of most MHC regions, such as HLA-DQB1 , HLA-DRA1 , HLA-DQA1 , were associated with pSS ( 36 ).…”

Dissecting the Cellular Landscape and Transcriptome Network in Viral Myocarditis by Single-Cell RNA Sequencing

“…To further determine the specific roles of potential transcripts that might contribute to CVB3 pathogenesis, we performed DGE in fibroblast clusters 1, 5, 6, and 8 of myocarditis and control ( Fig 4D ). These analyses revealed increased expression of complement proteins C3 and C4b ; Serpina3n, an accelerator of wound healing 53 ; Tmem176b , which controls DC maturation and also has a role in fibrosis 54 ; Tmem176a a negative regulator of DCs 55 ; and the anti-viral protein Ifitm 56 in all clusters of myocarditic mice ( Fig 4D ). Uniquely however, Sbno2 , a regulator of proinflammatory cascade 57 and Ly6a, also called Sca-1 , which has a known function in heart failure 58 , were increased in cluster 1 of myocarditic mice, as opposed to Gsta3, an inhibitor of TGF-β-induced epithelial and mesenchymal transition and fibronectin expression 59 , and Socs3 29 in cluster 5; Apod 52 in cluster 6; and Apoe in cluster 8 of myocarditic mice ( Fig 4D ).…”

“…Serpina3n, an accelerator of wound healing 53 ; Tmem176b, which controls DC maturation and also has a role in fibrosis 54 ; Tmem176a a negative regulator of DCs 55 ; and the anti-viral protein Ifitm 56 in all clusters of myocarditic mice (Fig 4D). Uniquely however, Sbno2, a regulator of proinflammatory cascade 57 and Ly6a, also called Sca-1, which has a known function in heart failure 58 , were increased in cluster 1 of myocarditic mice, as opposed to Gsta3, an inhibitor of TGF-β-induced epithelial and mesenchymal transition and fibronectin expression 59 S3).…”

Screening and Identification of Key Genes, Pathways, and Drugs Associated with Neuropathic Pain in Dorsal Horn: Evidence from Bioinformatic Analysis

“…For example, accumulating evidence reported that Tmem176a was involved in the remodeling of the dendritic cell after spinal cord injury. 23 Dendritic cells play a central role not only in the development of innate and adaptive immunity but also in the induction and maintenance of immune tolerance. 24 Previous studies showed that Tmem176a and Tmem176b could inhibit dendritic cell maturation and activation, together with abnormal functioning of cell‐mediated immunity.…”